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Item Higher Monocyte Count is Associated with 30-Day Case-Fatality in Intracerebral Hemorrhage(Springer, 2021) Mackey, Jason; Blatsioris, Ashley D.; Saha, Chandan; Moser, Elizabeth A.S.; Carter, Ravan J.L.; Cohen-Gadol, Aaron A.; Leipzig, Thomas J.; Williams, Linda S.; Neurology, School of MedicineBackground: Previous studies have suggested that elevated neutrophils, monocytes, and neutrophil-to-lymphocyte ratio (NLR) may be associated with poor outcomes in intracerebral hemorrhage (ICH). We sought to determine whether white blood cell (WBC) types were independently associated with poor outcome in ICH in a large cohort. Methods: We performed a retrospective study of primary ICH at two academic centers. Cases were identified via ICD-9 code and verified via physician review. We included only those patients with WBC types obtained within 24 h of ICH onset. Results: We identified 593 patients with primary ICH and WBC differentials in the first 24 h. Independent factors (OR, 95% CI) associated with 30-day case fatality were age > 80 (2.4 (1.4, 4.2)), p = 0.0023; NIHSS greater than median (3.9 (2.4, 6.3)), p < 0.0001; ICH volume quartiles (Q1: ref, Q2: 1.5 (0.7, 3.0), Q3: 3.2 (1.6, 6.6), Q4: 11.9 (5.3, 26.4)), p < 0.0001; non-lobar location (3.3 (1.9, 5.9)), p ≤ 0.0001; IVH (2.3 (1.4, 3.6)), p = 0.0005, monocytes greater than median (1.6 (1.0, 2.4)), p = 0.0457, and anticoagulant use (3.2 (1.8, 5.6)), p < 0.0001. Elevated NLR was not associated with higher case fatality. Conclusions: We found that elevated monocytes were independently associated with 30-day case fatality. Future studies will investigate whether there are subgroups of ICH patients, including those with particular blood or imaging biomarkers, in which WBC types might help predict poor outcome and provide targets for intervention.Item Implications of DPP4 modification of proteins that regulate stem/progenitor and more mature cell types(American Society of Hematology, 2013-07-11) Ou, Xuan; O'Leary, Heather A.; Broxmeyer, Hal E.; Microbiology & Immunology, IU School of MedicineDipeptidylpeptidase (DPP) 4 has the potential to truncate proteins with a penultimate alanine, proline, or other selective amino acids at the N-terminus. DPP4 truncation of certain chemokines, colony-stimulating factors, and interleukins have recently been linked to regulation of hematopoietic stem/progenitor cells, more mature blood cells, and other cell types. We believe that the potential role of DPP4 in modification of many regulatory proteins, and their subsequent effects on numerous stem/progenitor and other cell-type functions has not been adequately appreciated. This review addresses the potential implications of the modifying effects of DPP4 on a large number of cytokines and other growth-regulating factors with either proven or putative DPP4 truncation sites on hematopoietic cells, and subsequent effects of DPP4-truncated proteins on multiple aspects of steady-state and stressed hematopoiesis, including stem/progenitor cell, and more mature cell, function.Item Post-surgical changes in glucose uptake and enzyme activity in red and white blood cells(1972) O'Neill, Michael R.Item Restructuring of the Gut Microbiome by Intermittent Fasting Prevents Retinopathy and Prolongs Survival in db/db Mice(American Diabetes Association, 2018-09) Beli, Eleni; Yan, Yuanqing; Moldovan, Leni; Vieira, Cristiano P.; Gao, Ruli; Duan, Yaqian; Prasad, Ram; Bhatwadekar, Ashay; White, Fletcher A.; Townsend, Steven D.; Chan, Luisa; Ryan, Caitlin N.; Morton, Daniel; Moldovan, Emil G.; Chu, Fang-I; Oudit, Gavin Y.; Derendorf, Hartmut; Adorini, Luciano; Wang, Xiaoxin X.; Evans-Molina, Carmella; Mirmira, Raghavendra G.; Boulton, Michael E.; Yoder, Mervin C.; Li, Qiuhong; Levi, Moshe; Busik, Julia V.; Grant, Maria B.; Pediatrics, School of MedicineIntermittent fasting (IF) protects against the development of metabolic diseases and cancer, but whether it can prevent diabetic microvascular complications is not known. In db/db mice, we examined the impact of long-term IF on diabetic retinopathy (DR). Despite no change in glycated hemoglobin, db/db mice on the IF regimen displayed significantly longer survival and a reduction in DR end points, including acellular capillaries and leukocyte infiltration. We hypothesized that IF-mediated changes in the gut microbiota would produce beneficial metabolites and prevent the development of DR. Microbiome analysis revealed increased levels of Firmicutes and decreased Bacteroidetes and Verrucomicrobia. Compared with db/db mice on ad libitum feeding, changes in the microbiome of the db/db mice on IF were associated with increases in gut mucin, goblet cell number, villi length, and reductions in plasma peptidoglycan. Consistent with the known modulatory effects of Firmicutes on bile acid (BA) metabolism, measurement of BAs demonstrated a significant increase of tauroursodeoxycholate (TUDCA), a neuroprotective BA, in db/db on IF but not in db/db on AL feeding. TGR5, the TUDCA receptor, was found in the retinal primary ganglion cells. Expression of TGR5 did not change with IF or diabetes. However, IF reduced retinal TNF-α mRNA, which is a downstream target of TGR5 activation. Pharmacological activation of TGR5 using INT-767 prevented DR in a second diabetic mouse model. These findings support the concept that IF prevents DR by restructuring the microbiota toward species producing TUDCA and subsequent retinal protection by TGR5 activation.Item STAT4 Regulates the CD8+ Regulatory T Cell/T Follicular Helper Cell Axis and Promotes Atherogenesis in Insulin-Resistant Ldlr-/- Mice(American Association of Immunologists, 2017-11-15) Taghavie-Moghadam, Parésa L; Wassem, Tayab C.; Hattler, Julian; Glenn, Lindsey M.; Dobrian, Anca D.; Kaplan, Mark H.; Yang, Yi; Nurieva, Roza; Nadler, Jerry L.; Galkina, Elena V.; Pediatrics, School of MedicineThe metabolic syndrome and diabetic conditions support atherosclerosis, but the exact mechanisms for accelerated atherogenesis remain unclear. Although the proinflammatory role of STAT4 in atherosclerosis and diet-induced insulin resistance (IR) was recently established, the impact of STAT4 on atherogenesis in conditions of IR is not known. In this study, we generated Stat4-/-Ldlr-/- mice that were fed a diabetogenic diet with added cholesterol (DDC). DDC-fed Stat4-/-Ldlr-/- mice demonstrated improved glucose tolerance, insulin sensitivity, and a 36% reduction in atherosclerosis compared with Ldlr-/- controls. Interestingly, we detected a reduction in T follicular helper (Tfh) cells and plasma B cells but a sharp elevation in CD8+ regulatory T cells (Tregs) in spleens and aortas of Stat4-/-Ldlr-/- mice compared with Ldlr-/- mice. Similarly, STAT4 deficiency supported CD8+ Treg differentiation in vitro. STAT4-deficient CD8+ Tregs suppressed Tfh cell and germinal center B cell development upon immunization with keyhole limpet hemocyanin, indicating an important role for STAT4 in CD8+ Treg functions in vivo. Furthermore, adoptive transfer of Stat4-/-Ldlr-/- CD8+ Tregs versus Ldlr-/- CD8+ Tregs resulted in a significant reduction in plaque burden and suppression of Tfh cell and germinal center B cells in DDC-fed Ldlr-/- recipients. STAT4 expression in macrophages (MΦs) also affected the Tfh/CD8+ Treg axis, because conditioned media from Stat4-/-Ldlr-/- MΦs supported CD8+ Treg differentiation, but not Tfh cell differentiation, in a TGF-β-dependent manner. These findings suggest a novel mechanism by which STAT4 supports atherosclerosis in IR Ldlr-/- mice via STAT4-dependent MΦs, as well as cell-intrinsic suppression of CD8+ Treg generation and functions and maintenance of Tfh cell generation and the accompanying humoral immune response.